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bioRxiv · 10.1101/588319

Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia

Milne, P.·Wilhelm-Benartzi, C.·Grunwald, M. R.·Bigley, V.·Publicover, A.·Pagan, S.·Marr, H.·Jones, G.·Dickinson, A.·Grech, A.·Burnett, A.·Russell, N.·Levis, M.·Knapper, S.·Collin, M.
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Abstract

Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3+AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p < 0.0001). Day 26 Flt3L was also associated with survival: Flt3L [&le;] 291pg/ml was associated with inferior event-free survival; and, Flt3L >1185pg/ml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC=\"FIGDIR/small/588319_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (21K):\norg.highwire.dtl.DTLVardef@132f3f3org.highwire.dtl.DTLVardef@2e033eorg.highwire.dtl.DTLVardef@d70598org.highwire.dtl.DTLVardef@b0648a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Milne, P., Wilhelm-Benartzi, C., Grunwald, M. R., Bigley, V., Publicover, A., Pagan, S., Marr, H., Jones, G., Dickinson, A., Grech, A., Burnett, A., Russell, N., Levis, M., Knapper, S., Collin, M.. 2019-03-25. Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia. https://doi.org/10.1101/588319

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